Activated macrophages or monocytes are an important arm of an immune or inflammatory response. These white blood cells ingest microbes, produce and release (intracellularly) reactive oxygen species, and secrete various cytokines that upregulate immune and inflammatory responses of an infected mammal to the microbe or microbes causing the infection. Certain microbes, however, have developed mechanisms to circumvent the anti-microbial activity of activated macrophages/monocytes. Such microbes are referred to as macrophage pathogens, and include any microorganism that replicates or proliferates within host macrophage or monocytic cells as their exclusive or primary host cells.
Examples of macrophage pathogens include Leishmania spp., Trypanosoma cruzi, Mycobacterium tuberculosis and Mycobacterium leprae, as well as the protozoan Toxoplasma gondii. The fungi Histoplasma capsulatum, Candida albicans, Candida parapsilosis, and Cryptococcus neoformans can also be considered macrophage pathogens. Additional examples include the Rickettsia, for example, R. prowazekii, R. coronii, and R. tsutsugamushi. Infectious disease in which one or more macrophage pathogen is present can also occur.
One cytokine which is associated with both immune regulation and control of macrophage activation is Transforming Growth Factor-.beta. (TGF-.beta.). This 24 Kd protein is produced by many cells, including B cells, T cells and activated macrophages. TGF-.beta. has been implicated as a mediator of immunosuppression, as inhibiting Interleukin-2 (IL-2) receptor induction, as mediating Interleukin-1 (IL-1) induced thymocyte proliferation, and other activities. In addition, TGF-.beta. has the ability to inhibit cytokine-induced macrophage activation, and to suppress production of reactive oxygen and nitrogen intermediates. Thus, there is a need in the art to determine if TGF-.beta. antagonists will be effective as anti-microbial agents in vivo.